There is increasing evidence that early-life exposures to inorganic arsenic can cause disease later in life. However, nearly all of these studies have evaluated arsenic exposures at ppm (mg/L) concentrations when environmentally relevant concentrations of arsenic are one thousandths these levels. Preliminary results from our laboratory indicate that early life exposures to environmentally relevant concentrations of arsenic induce obesity, hyperglycemia and fatty liver disease in male, but not female, mice in adulthood. We hypothesize those developmental exposures to lower levels of arsenic cause oxidative stress and DNA hypomethylation, resulting in persistent changes in gene expression critical to the development of fatty liver disease and symptoms consistent with metabolic syndrome. Several studies have demonstrated that high-dose arsenic exposures induce oxidative stress and decrease genomic DNA methylation, but it is unknown whether these effects (1) occur following in utero and early postnatal exposure to low levels of arsenic;and (2) result in long-term epigenetic alterations that increase risk for developing obesity, hyperglycemia and liver disease later in life. Since females are much less susceptible to oxidative stress and have a greater capacity to methylate both DNA and arsenic, our proposed mechanisms may explain why male offspring are more susceptible to developing arsenic-induced obesity, hyperglycemia and fatty liver disease. Studies within this proposal will determine whether exposure to 50 or 500 ppb sodium arsenite in maternal drinking water (given 1 week prior to mating until PND 21) induces hepatic and placental oxidative stress, decreased global and gene-specific DNA methylation, and/or altered expression levels of genes that play important roles in obesity, diabetes and fatty liver disease. As such, this AREA (R15) proposal addresses the Challenge Topic 15-ES-102, the developmental basis of human disease. Furthermore, receipt of an AREA award will support the PI efforts to establish a productive research program at Bates College while providing many opportunities for undergraduate students to plan studies, work with laboratory animals, collect and analyze data, and present their work to the scientific community. PUBLIC HEALTH RELEVANCE: This project seeks to determine the cellular and molecular mechanisms by which developmental exposures to lower-levels of arsenic increase obesity, fatty-liver disease and symptoms of diabetes in adult mice. This information can be used to better determine the risk posed to humans exposed to arsenic, possibly influencing regulatory standards that are set to ensure safe drinking water. This work could also lead to the identification of specific targets for new drug treatment strategies in the fight against obesity, fatty-liver disease and type-2 diabetes.